Amiloride is a K+-sparing diuretic that effectively inhibits the Na+/H+ transporter in the plasma membrane of most mammalian cells. We have examined the effects of amiloride on the progression of apoptosis in HL-60 cells induced by camptothecin (CAM), cycloheximide (CHX) and 20 Gy gamma irradiation. Data presented show that effects of amiloride on membrane Na+/H+ transporter activity and intracellular pH can potentially affect apoptotic signaling cascades, leading to a retardation in the rate of progression to an apoptotic cell death. Results also point to the involvement of intracellular pH and Ca2+ in the regulation of apoptotic endonuclease activity, and the need for a functional Na+/H+ exchanger for the induction of apoptosis